阅读说明：本技术 一类含异丙醇芳香醚类结构的紫檀芪胺类化合物及其制备方法和应用 (Pterostilbene amine compounds containing isopropanol aromatic ether structure and preparation method and application thereof ) 是由 王培义 王明伟 周丽 齐普应 田欢 雷立 王优丹 杨松 薛伟 于 2020-11-24 设计创作，主要内容包括：本发明涉及一类含异丙醇芳香醚类结构的紫檀芪胺类化合物及其制备方法和应用。该化合物具有如通式(I)所示的结构：本发明以紫檀芪类化合物为基础,将含有各类芳香胺和杂环胺的片段引入到此体系中,合成一系列含各种胺类结构的异丙醇芳香醚紫檀芪类化合物,该化合物对植物病原微生物具有良好的抑制作用,尤其对植物病原细菌如水稻白叶枯病菌、柑橘溃疡病菌、猕猴桃溃疡病菌和植物病原真菌如葡萄座腔菌、水稻纹枯病菌、火龙果炭疽病菌等具有良好的抑制效果。(The invention relates to a pterostilbene amine compound containing an isopropanol aromatic ether structure and a preparation method and application thereof. The compound has a structure shown as a general formula (I):)

1. A pterostilbene amine compound containing an isopropanol aromatic ether structure or a stereoisomer thereof, or a salt or a solvate thereof is characterized in that: the compound has a structure shown as a general formula (I):

wherein

R₁And R₂Each independently selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl containing one heteroatom, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl, R₁And R₂Each of which may be fused to form a ring.

2. The pterostilbene amine compound containing an isopropanol aromatic ether structure according to claim 1, or a stereoisomer thereof, or a salt or solvate thereof, wherein:

R₁and R₂Each independently selected from hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstitutedOne or more substituted C6-C10 heteroaryl, wherein substituted refers to substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; more preferably, R₁And R₂Each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-heptyl, 2-methylhexanyl, 3-methylhexanyl, 2, 4-dimethylpentyl, 2, 3-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 3-ethylpentyl, 2, 3-trimethylbutyl, 1-dimethyl, 1, 5-dimethylhexyl, 1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, hydroxyethyl, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, n-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and neopentyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2, 3-dichlorobenzyl, 2, 4-dichlorobenzyl, 2, 5-dichlorobenzyl, 3, 4-dichlorobenzyl, 3, 5-dichlorobenzyl, 2, 3-difluorobenzyl, 2, 4-difluorobenzyl, 2, 5-difluorobenzyl, 3, 4-difluorobenzyl, 3, 5-difluorobenzyl, 2-furanmethylene, 3-furanmethylene, 2-thiophenemethylene, 3-thiophenemethylene, 2-pyridinemethylene, 3-pyridinemethylene, 4-pyridinemethylene, phenoxyphenyl; when R is₁And R₂When fused into a ring, is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-benzylpiperazinyl, 1- (2-methoxybenzyl) piperazinyl, 1- (3-methoxybenzyl) piperazinyl, 1- (4-methoxybenzyl) piperazinyl, 1- (2-methylbenzyl) piperazineA group, 1- (3-methylbenzyl) piperazinyl group, 1- (4-methylbenzyl) piperazinyl group, 1- (2-chlorobenzyl) piperazinyl group, 1- (3-chlorobenzyl) piperazinyl group, 1- (4-chlorobenzyl) piperazinyl group, 1- (2-fluorobenzyl) piperazinyl group, 1- (3-fluorobenzyl) piperazinyl group, 1- (4-fluorobenzyl) piperazinyl group, 1- (2-bromobenzyl) piperazinyl group, 1- (3-bromobenzyl) piperazinyl group, 1- (4-bromobenzyl) piperazinyl group, 1- (2-aminobenzyl) piperazinyl group, 1- (3-aminobenzyl) piperazinyl group, 1- (4-aminobenzyl) piperazinyl group, 1- (2-hydroxybenzyl) piperazinyl group, a salt thereof, 1- (3-hydroxybenzyl) piperazinyl, 1- (4-hydroxybenzyl) piperazinyl, 1- (2-nitrobenzyl) piperazinyl, 1- (3-nitrobenzyl) piperazinyl, 1- (4-nitrobenzyl) piperazinyl, 1- (2-trifluoromethylbenzyl) piperazinyl, 1- (3-trifluoromethylbenzyl) piperazinyl, 1- (4-trifluoromethylbenzyl) piperazinyl, 1- (2-methylbenzyl) piperazinyl, 1- (3-methylbenzyl) piperazinyl, 1- (4-methylbenzyl) piperazinyl.

3. The pterostilbene amine compound containing an isopropanol aromatic ether structure according to claim 1, characterized by being selected from the following compounds:

4. an intermediate compound for preparing the pterostilbene amine compound containing the isopropanol aromatic ether structure, or a stereoisomer thereof, or a salt or a solvate thereof according to claim 1, wherein the intermediate compound is characterized by comprising the following components in percentage by weight:

5. the method for preparing pterostilbene amine compound containing isopropanol aromatic ether structure or stereoisomer thereof, or salt or solvate thereof containing various types of tertiary amine structure as claimed in any one of claims 1 to 3, characterized by comprising the following steps:

wherein R is₁、R₂As described above.

6. A composition characterized by comprising a compound of any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).

7. Use of a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 7, for controlling an agricultural pest, preferably a bacterial or fungal disease of a plant; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, tobacco bacterial wilt, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight, blueberry root rot, grape lumen bacteria, dragon fruit anthracnose and rice sheath blight.

8. A method for controlling agricultural pests is characterized in that: allowing a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 7 to act on the noxious substances or their living environments; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, tobacco bacterial wilt, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight, blueberry root rot, grape lumen bacteria, dragon fruit anthracnose and rice sheath blight.

9. A method for protecting a plant from an agricultural pest comprising a method step wherein the plant is contacted with a compound of any one of claims 1-3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 7.

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to a pterostilbene amine compound containing an isopropanol aromatic ether structure and a preparation method and application thereof.

Background

Bacterial and fungal diseases of plants, such as bacterial blight of rice, bacterial wilt of capsicum, leaf spot of Chinese cabbage, bacterial wilt of tobacco, canker of citrus, canker of kiwi fruit, gray mold of cucumber, blight of capsicum, sclerotinia rot of colza, scab of wheat, late blight of potato, root rot of blueberry, botrytis cinerea, anthracnose of dragon fruit, banded sclerotial blight of rice and the like, are several important diseases which are caused by plant pathogenic bacteria and fungi and affect the production of crops, and are mainly manifested by symptoms of necrosis, fusarium wilt, rot and the like. The traditional bactericide is used, so that the drug resistance of the plant pathogenic microorganisms is increased, and the environment and the safety of crops are influenced. Therefore, there is an urgent need to develop a novel fungicide having high activity and high selectivity.

The plant source natural product with biological activity is an important resource for creating and researching new pesticides. Most of botanical pesticides have low toxicity or even no toxicity to mammals, and are safe to human and livestock in use. Pterostilbene (PSB) is a trans-stilbene compound and is a methylated derivative of resveratrol. According to the reports of the literature, pterostilbene is an effective component derived from pterocarpus indicus, blueberries, grapes, Pterocarpus marsupium and other plants, and has wide biological effects of resisting cancer, resisting inflammation, resisting oxidation, relieving pain and the like. In addition, the PSB has the advantages of simple synthesis process, convenient operation, low production cost and good industrial application prospect. In order to search for a natural lead compound with high-efficiency antibacterial activity, the invention synthesizes a series of pterostilbene amine compounds containing isopropanol aromatic ether structures on the basis of pterostilbene, inspects the biological activity of the compounds for resisting plant pathogenic microorganisms, and provides an important scientific basis for research, development and creation of novel bactericides.

The research on the biological activity of the pterocarpus santalinus stilbene compounds progresses as follows:

in 2011, Victor s. sobolev et al [ Victor s. sobolev, Shabana i.khan, Nurhayat Tabanca, David e.wedge, Susan p.maniy, Stephen j.cutler, Monique r.coy, James j.becnel, Scott a.neff, and James b.gloer.biological Activity of peanout (araachis hypothoae) Phytoalexins and Selected Natural and Synthetic Stilbenoids [ j.agric.Food.2011, 59, 1673. assamica ] used mass spectrometry, in vitro Activity assay, cytotoxicity, anti-inflammatory Activity assay, opioid receptor and dockerin etc. (i.e. two-defense compounds) to protect against fungal diseases and fungal pathogens, and have anti-inflammatory effects on fusarium oxysporum, etc. In addition, the insecticidal composition has remarkable insecticidal activity on adult mosquitoes and larvae, and the lethality rate on the mosquitoes is 100% at 6.25 mu g/mL.

In 2012, Carole Lambert et al [ Carole Lambert, Jonathan Bisson, Pierre wafdo-Teguo, Yorgos Papasitamoulis, Tristan Richard, Marie-France Corio-Costet, Jean-Michel Melilon, and Stephanie Cluzet, Phenolics and the same antibacterial Role in Grapevine Wood Decay: researches on Focus on the botryosphaeria Family [ J ]. J.Agric.food chem.2012, 60, 11859-11868 ] through guaiacol, SEM, grape tree living body inoculation and other modes report that the stilbene polyphenol compound has obvious bacteriostatic action on grape cavity bacteria (botryosphaeria) causing grape tree trunk rotting.

In 2015, Weilin Jian et al [ Weilin Jian, Daohang He, Pinggen Xi, and Xinwei Li. Synthesis and Biological Evaluation of Novel fluoride-Containing Stilbene Derivatives as a fungal ingredient and measuring the Biological activity thereof, various experimental methods such as structure-activity relationship analysis, mycelial morphological observation, membrane permeability, hyphal respiration and the like show that the target compound has a remarkable inhibitory effect on cucumber anthracnose and cucumber downy mildew, and particularly, when the compound 9 is 400 μ g/mL, the pesticide effect (83.4 +/-1.3%) and the commercial pesticide 80% carbendazim powder (82.7 +/-1.7%) have a relatively high development prospect.

In 2017, Wee Xiaoan Lee et al [ Wee Xiaoan Lee, Dayang Fredalina Basri and Ahmad Rohi ghazali. bacterial Effect of Pterostilbene Alone and in Combination with Gentamicin against Human Pathogenic Bacteria [ J ]. molecules.2017, 22, 463 ] study the biological activity of Pterostilbene against Bacteria under both single and combined Gentamicin conditions by microdilution, checkerboard and time-lethal kinetic analysis methods. The result shows that when the concentration of pterostilbene and gentamicin is 0.5 × MIC (minimal inhibitory concentration) value in 2-8h, the pterostilbene and gentamicin have no significant difference compared with the effect on gentamicin of staphylococcus aureus, escherichia coli and agrobacterium viridans, and the pterostilbene and gentamicin have the effect of delaying bacterial drug resistance.

In 2019, Giovanna Simonetti et al [ Giovanna Simonetti, Cleof Palocci, Alisio Valletta, Olga Kolesova, Laura Chonopoulouu, Livia Donati, Antonio Di Nitto, Elisa Brasili, Pierpaolo Tomai, Alessandra Gentili and Gabriella Pasqua. Anellata-Candida Biofilm Activity of Pterostilb or crack trace from Non-Fermented Grape pore Enporous Nanoparticles [ J ]. macromolecules.2019, 24, 2070 ] were found to have cell wall adhesion enhancing function against Candida albicans, Candida albicans and biomembrane when the bioactivity of the Nanoparticles was measured.

2019, Lindsey G Horty et al [ Lindsey G Horty, John F Daeuble, Scott Castetter, Monica B Olson, Frank J Wessels and Nick X Wang. Synthesis, stability and inductive activity of 2-arylstilbenes [ J].Pest Manag Sci.2019；75：3015-3023.]2-stilbene compounds were synthesized and their biological activity was measured and found to be at 50. mu.g/cm²And 12.5. mu.g/cm²At concentration, the target compound of the Z formula has higher insecticidal activity on asparagus caterpillar and trichodina. Meanwhile, injection experiments are carried out on three-instar asparagus caterpillar larvae, and the fact that the compound Z-7g has the effect of quickly knocking down, causes insect body tremor of pests within 90min, has the characteristic of a nervous system mode, and does not have the effect of an HMG-CoA reductase inhibitor is found.

In 2020, David Righi et al [ David Righi, Robin Huber, Alexey Koval, Laurence Marcourt, Sylvain Schnee,Le Floch，Verena Ducret，Remo Perozzo，Concetta C.de Ruvo，Nicole Lecoultre，Emilie Michellod，Samad N.Ebrahimi，Elisabeth Rivara-Minten，Vladimir L.Katanaev，Karl Perron，Jean-Luc Wolfender，Katia Gindro，and Emerson F.Queiroz.Generation of Stilbene Antimicrobials against Multiresistant Strains of Staphylococcus aureus through Biotransformation by the Enzymatic Secretome of Botrytis cinerea[J].J.Nat.Prod.2020，83，2347-2356.]studies find that stilbene compounds secreted by the enzyme catalysis of the botrytis cinerea have better antibacterial activity against staphylococcus aureus strains of various antibiotics.

Disclosure of Invention

The invention aims to provide a pterostilbene amine compound containing an isopropanol aromatic ether structure, or a stereoisomer, a salt or a solvate thereof.

Another object of the present invention is to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt or solvate thereof, and a preparation method thereof.

It is still another object of the present invention to provide a composition comprising the above compound or a stereoisomer thereof, or a salt or solvate thereof.

It is a further object of the present invention to provide the above compounds or stereoisomers thereof, or salts or solvates thereof, or the use of said compositions.

The invention also aims to provide a method for controlling crop pests by using the compound or the stereoisomer thereof, the salt thereof or the solvate thereof or the composition.

In order to realize the purpose, the invention adopts the following technical scheme:

a pterostilbene amine compound containing an isopropanol aromatic ether structure or a stereoisomer thereof, or a salt or a solvate thereof has a structure shown as a general formula (I):

wherein

R₁And R₂Each independently selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl containing one heteroatom, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl, R₁And R₂Each of which may be fused to form a ring.

Preferably, R₁And R₂Each independently selected from one or more of hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C6-C10 heteroaryl, wherein the substituted refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl; more preferably, R₁And R₂Each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-heptyl, 2-methylhexanyl, 3-methylhexanyl, 2, 4-dimethylpentyl, 2, 3-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 3-ethylpentyl, 2, 3-trimethylbutyl, 1-dimethyl, 1, 5-dimethylhexyl, 1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, hydroxyethyl, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, n-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and neopentyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2, 3-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3,2, 4-dichlorobenzyl, 2, 5-dichlorobenzyl, 3, 4-dichlorobenzyl, 3, 5-dichlorobenzyl, 2, 3-difluorobenzyl, 2, 4-difluorobenzyl, 2, 5-difluorobenzyl, 3, 4-difluorobenzyl, 3, 5-difluorobenzyl, 2-furanmethylene, 3-furanmethylene, 2-thiophenemethylene, 3-thiophenemethylene, 2-pyridinemethylene, 3-pyridinemethylene, 4-pyridinemethylene, phenoxyphenyl; morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-benzylpiperazinyl, 1- (2-methoxybenzyl) piperazinyl, 1- (3-methoxybenzyl) piperazinyl, 1- (4-methoxybenzyl) piperazinyl, 1- (2-methylbenzyl) piperazinyl, 1- (3-methylbenzyl) piperazinyl, 1- (4-methylbenzyl) piperazinyl, 1- (2-chlorobenzyl) piperazinyl, piperazinyl, 1- (3-chlorobenzyl) piperazinyl, 1- (4-chlorobenzyl) piperazinyl, 1- (2-fluorobenzyl) piperazinyl, 1- (3-fluorobenzyl) piperazinyl, 1- (4-fluorobenzyl) piperazinyl, 1- (2-bromobenzyl) piperazinyl, 1- (3-bromobenzyl) piperazinyl, 1- (4-bromobenzyl) piperazinyl, 1- (2-aminobenzyl) piperazinyl, 1- (3-aminobenzyl) piperazinyl, 1- (4-aminobenzyl) piperazinyl, 1- (2-hydroxybenzyl) piperazinyl, 1- (3-hydroxybenzyl) piperazinyl, 1- (4-hydroxybenzyl) piperazinyl, 1- (2-nitrobenzyl) piperazinyl, 1- (3-nitrobenzyl) piperazinyl, 1- (4-nitrobenzyl) piperazinyl, 1- (2-trifluoromethylbenzyl) piperazinyl, 1- (3-trifluoromethylbenzyl) piperazinyl, 1- (4-trifluoromethylbenzyl) piperazinyl, 1- (2-methylbenzyl) piperazinyl, 1- (3-methylbenzyl) piperazinyl, 1- (4-methylbenzyl) piperazinyl.

Most preferably, the compound is selected from the following specific compounds:

the invention also provides an intermediate compound for preparing the pterostilbene amine compound containing the isopropanol aromatic ether structure or a stereoisomer thereof, or a salt or a solvate thereof, which is characterized by comprising the following components in parts by weight:

the invention also provides a preparation method of the pterostilbene amine derivative containing the isopropanol aromatic ether structure or a stereoisomer thereof, or a salt or a solvate thereof, which is characterized by comprising the following steps:

wherein R is₁、R₂As described above.

The invention also provides a composition containing the compound or the stereoisomer or the salt or the solvate thereof, and an agriculturally acceptable auxiliary agent or bactericide, pesticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).

The compound or the stereoisomer thereof, or the salt or the solvate thereof, or the composition can be used for controlling agricultural pests, preferably bacterial or fungal diseases of plants; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogen, sclerotinia rot of colza, wheat scab pathogen, potato late blight pathogen and blueberry root rot.

The invention also provides a method for preventing and controlling agricultural pests, which enables the compound or the stereoisomer thereof, the salt thereof or the solvate thereof, or the composition to act on the pests or the living environment thereof; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, tobacco bacterial wilt, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight, blueberry root rot, grape lumen bacteria, dragon fruit anthracnose and rice sheath blight. .

The present invention also provides a method for protecting a plant from an agricultural pest comprising a method step wherein a plant is contacted with the compound or stereoisomer thereof, or salt or solvate thereof, or the composition.

The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C_1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C_1-6Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

"alkenyl" is a hydrocarbon group that includes both straight and branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. E.g. "C_2-6Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Of alkenyl groupsExamples include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

"alkynyl" is intended to include both straight and branched chain hydrocarbons having one or more carbon-carbon triple bonds at any stable point in the chain. E.g. "C_2-6Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N). When referring to substitution, especially polysubstitution, it is meant that the substituents are multiple in each position on the indicated group, e.g. dichlorophenyl means 1, 2-dichlorophenyl, 1, 3-dichlorophenyl, 1, 4-dichlorophenyl and 2, 4-dichlorophenyl.

Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O)₂H or S (O) H group.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.

The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.

The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl; even if the halo in a haloalkyl group is specified as fluoro, chloro, bromo, iodo, the same refers to a substituted alkyl group having one or more fluoro, chloro, bromo, iodo substituents.

The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with ═ O (oxygen), as valency permits.

Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention.

Preferably, C₁-C₁₀Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; c₁-C₁₀Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomers thereof; c₂-C₅Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl, and isomers thereof.

When reference is made to substituents being alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino as specified, one to three of the above substituents are meant. Such as methylphenyl refers to phenyl substituted with one to three methyl groups.

By adopting the technical scheme, the invention synthesizes a series of pterostilbene derivatives containing isopropanol aromatic ether structures on the basis of pterostilbene compounds, and discovers that the compounds have good inhibition effects on plant pathogenic bacteria and fungi, have good inhibition effects on pathogenic bacteria [ such as Xanthomonas oryzae pv. oryzae, Xoo, Xanthomonas canker, etc. ], have remarkable inhibition effects on pathogenic fungi [ such as Botryosphaeria dothidea, B.d ], Pityrosporum ovale (Coletonrichun gloeosporoides, C.g), Rhizoctonia solani (Rhizoctonia solani, R.s), and the like ], and provide important scientific basis for research and development and creation of new pesticides.

Examples

The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.

Example 1: preparation of pterostilbene epoxy intermediate 1

1.0mmol of pterostilbene and 1.2mmol of potassium carbonate were added to a 25mL round bottom flask containing 10mL anhydrous DMF and stirred at room temperature until pterostilbene was completely dissolved. 1.3mmoL of propylene bromide oxide was further added dropwise thereto, and the mixture was stirred at 35 ℃ for 8 hours to complete the reaction. Stopping the reaction, adding 50mL of ethyl acetate, washing an organic layer with saturated ammonium chloride water, washing with saturated saline water, drying with anhydrous sodium sulfate, desolventizing, and carrying out column chromatography to obtain a white solid with the yield of 88.5%. The nuclear magnetic data are:¹H NMR(400MHz，CDCl₃)δ7.44(d，J＝8.7Hz，2H，phenyl-H)，7.04(d，J＝16.3Hz，1H，phenyl-CH＝CH)，6.91(dd，J＝12.5，3.7Hz，3H，phenyl-CH＝CH&phenyl-H)，6.66(d，J＝2.2Hz，2H，phenyl-H)，6.39(t，J＝2.2Hz，1H，phenyl-H)，4.23(dd，J＝11.0，3.0Hz，1H，1/2phenyl-O-CH₂)，3.94(dd，J＝11.0，5.7Hz，1H，1/2phenyl-O-CH₂)，3.83(s，6H，2O-CH₃)，3.37-3.34(m，1H，O-CHCH₂)，2.92-2.89(m，1H，1/2O-CH ₂CH)，2.76(dd，J＝4.9，2.6Hz，1H，1/2O-CH ₂CH)；¹³C NMR(101MHz，CDCl₃)δ161.0，158.3，139.6，130.4，128.6，127.9，126.9，114.8，104.4，99.7，68.8，55.4，50.2，44.7.

example 2: (E) -1-amino-3- (4- (3, 5-dimethoxystyryl) phenoxy) propan-2-ol

Adding 1.0mmoL of pterostilbene epoxy intermediate 1 and 1.1mmoL of potassium carbonate into a round-bottom flask containing 5mL of isopropanol, stirring at room temperature until the intermediate 1 is completely dissolved, then dropwise adding 2.0mmoL of ammonia water, heating to 60 ℃, reacting for 6 hours, stopping the reaction, removing the solvent by reduced pressure distillation, and carrying out column chromatography to obtain a white solid with the yield of 85.1%.

Other objective compounds were synthesized by following the procedures of examples 1 and 2, using the corresponding starting materials or substituents. The structure, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized pterostilbene amine compound containing the isopropanol aromatic ether structure are shown in table 1, and the physicochemical properties are shown in table 2.

Nuclear magnetic resonance hydrogen, carbon and high resolution mass spectral data for the compounds of table 1

TABLE 2 physicochemical Properties of the target Compounds

Pharmacological example 1:

EC₅₀(medianeffective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to compounds, and is also an important parameter for setting the concentration of the compounds when researching the action mechanism of target compounds. In the concentration gradient experiment, proper 5 concentrations are set by a double dilution method, finally the inhibition rate of the medicament on plant pathogenic bacteria and the medicament concentration are converted into paired numerical values, a toxicity curve is obtained through SPSS software regression analysis, and EC is calculated₅₀。

Testing the effective medium concentration EC of target compound on plant pathogenic bacteria by adopting turbidity method₅₀The test subjects were rice bacterial blight (Xoo), citrus canker (Xac) and kiwi canker (Psa). DMSO was dissolved in the medium as a blank control. Placing rice bacterial leaf blight bacteria (in M210 solid culture medium) in NB culture medium, and shake culturing in constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for use; placing citrus canker pathogen (on M210 solid medium) into NB medium; placing Actinidia kolomikta canker (on M210 solid culture medium) into NB culture medium, and shake-culturing in constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for use. 5mL of toxic NB liquid culture medium prepared by the medicament (compound) into different concentrations (for example: 100, 50, 25, 12.5, 6.25 μ g/mL) is added into a test tube, 40 μ L of NB liquid culture medium containing plant disease bacteria is respectively added, and the mixture is shaken in a constant temperature shaking table with the temperature of 28-30 ℃ and the rpm of 180rpm, wherein the bacterial blight pathogenic bacteria of rice is cultured for 48h, the citrus canker pathogenic bacteria are cultured for 48h, and the kiwi canker pathogenic bacteria are cultured for 24 h. The bacterial liquid of each concentration is used for determining OD on a microplate reader₅₉₅Value, and additionally determining the OD of the corresponding concentration of the sterilized NB-containing liquid medium₅₉₅The value is obtained.

Corrected OD value-bacteria-containing medium OD value-sterile medium OD value

Percent inhibition is [ (OD value of control medium liquid OD value after correction-OD value of medium containing toxin corrected)/OD value of control medium liquid OD value after correction ] × 100

The examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.

TABLE 3 aromatic ethers containing isopropanolPterostilbene amine compound with similar structure EC against plant pathogenic bacteria₅₀

As can be seen from Table 3, the target compounds showed good bacteriostatic activity against plant pathogenic bacteria (such as Padina vulgare, Citrus canker and Actinidia chinensis) in the in vitro test. Compounds 10, 14, 17, 26, 32 and 36 showed excellent inhibitory activity against fusarium oxysporum f.sp.oryzae pv. oryzae, Xoo, with an EC50 of 0.879-1.52 μ g/mL; compounds 3, 4, 10, 21, 22, 33 and 38 showed excellent inhibitory activity against citrus canker pathogen (xathomonas axonopodis pv. citri, xaca) with EC50 of 3.88-5.73 μ g/mL; the compounds 4, 7 and 31 show excellent inhibitory activity on Actinidia (Pseudomonas syringaePv. Actinidiae, Psa), and have EC50 of 3.04-4.03 μ g/mL, and can be used for preparing pesticides for resisting plant pathogenic bacteria.

Pharmacological example 2:

the antibacterial activity of the compound on plant pathogenic fungi and oomycetes such as plasmodiophora dothidea (B.d), dragon fruit anthracnose (Colletotrichun gloeosporioides, C.g), Rhizoctonia solani (Rhizoctonia solani, R.s) and the like is measured on a PDA culture medium by adopting a mycelium growth rate inhibition method, and the strains are activated in advance. Weighing a compound to be detected by a ten-thousandth balance, adding 1mL of DMSO (dimethyl sulfoxide), dissolving, transferring to a 15mL sterilized centrifuge tube in a sterile operating platform, adding 9mL of water (Tween-20) for dissolving, pouring 10mL of water into a culture medium, uniformly mixing, and uniformly subpackaging into 9 culture dishes for cooling for later use; preparing bacterial colony growing normally into bacterial cake with sterilized punch (5mm) in sterile operating platform, reversing the bacterial cake in the center of culture medium with inoculating ring, culturing at 28 deg.C for 3-5 days, and allowing the bacterial colony to grow to the wholeThe plate diameter was 2/3 times measured with a ruler in a cross-hatch manner, and the colony diameter was calculated as an average value. At the initial stage, 25 mu g/mL is selected as a primary screening concentration, and EC is carried out on the compound when the corresponding germ inhibition rate of the compound is more than 50% at the concentration₅₀The test was carried out to find the hypha growth inhibition rate according to the following formula. Azoxystrobin, boscalid and fluopyram were tested together as control agents. The calculation formula is as follows:

inhibition ratio (%) - (C1-C2)/(C1-0.5) × 100 formula:

c1: control colony diameter, i.e., DMSO-treated colony diameter;

c2: the diameter of the treated colony is the diameter of the colony treated by adding medicine;

0.5: the diameter of the mother fungus cake.

The examples of the present invention are given to illustrate the technical solutions of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 4.

TABLE 4 EC of pterostilbene amines against phytopathogenic fungi containing isopropyl alcohol aromatic ether structure₅₀

As can be seen from Table 4, the target compounds showed good bacteriostatic activity against plant pathogenic fungi (Staphylocoma botrytis, Rhizoctonia solani and Pityrosporum ovale) in the in vitro test. Compound 35 showed excellent inhibitory activity against Staphylococus (B.d), EC thereof₅₀25.2. mu.g/mL, although lower than the control azoxystrobin, with the commercial drug fluopyramIs equivalent to and far superior to boscalid; compounds 1, 2 and 35 showed good inhibitory activity against Pityrosporum ovale (Colletotrichun gloeosporioides, C.g), with EC thereof₅₀11.6-13.4 mug/mL, and the activity is far higher than that of azoxystrobin and fluopyram although the activity is lower than that of the commercial boscalid; compound 35 has good bacteriostatic activity on Rhizoctonia solani (R.s), and EC thereof₅₀The antibacterial activity of the compound is 12.1 mu g/mL, although the antibacterial activity is slightly inferior to that of the control drugs of boscalid and fluopyram, the compound is far superior to azoxystrobin, and the compound can be used for preparing pesticides for resisting plant pathogenic fungi.